(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Chemical-and-Drug-Induced-Liver-Injury

The current guidelines of statins for primary cardiovascular disease (CVD) prevention were based on results from systematic reviews and meta-analyses that suffer from limitations.. We searched in PubMed for existing systematic reviews and individual open-label or double-blinded randomized controlled trials that compared a statin with a placebo or another, which were published in English until January 01, 2018. We performed a random-effect pairwise meta-analysis of all statins as a class and network meta-analysis for the specific statins on different benefit and harm outcomes.. In the pairwise meta-analyses, statins as a class showed statistically significant risk reductions on non-fatal MI (risk ratio [RR] 0.62, 95% CI 0.53-0.72), CVD mortality (RR 0.80, 0.71-0.91), all-cause mortality (RR 0.89, 0.85-0.93), non-fatal stroke (RR 0.83, 0.75-0.92), unstable angina (RR 0.75, 0.63-0.91), and composite major cardiovascular events (RR 0.74, 0.67-0.81). Statins increased statistically significantly relative and absolute risks of myopathy (RR 1.08, 1.01-1.15; Risk difference [RD] 13, 2-24 per 10,000 person-years); renal dysfunction (RR 1.12, 1.00-1.26; RD 16, 0-36 per 10,000 person-years); and hepatic dysfunction (RR 1.16, 1.02-1.31; RD 8, 1-16 per 10,000 person-years). The drug-level network meta-analyses showed that atorvastatin and rosuvastatin were most effective in reducing CVD events while atorvastatin appeared to have the best safety profile.. All statins showed statistically significant risk reduction of CVD and all-cause mortality in primary prevention populations while increasing the risk for some harm risks. However, the benefit-harm profile differed by statin type. A quantitative assessment of the benefit-harm balance is thus needed since meta-analyses alone are insufficient to inform whether statins provide net benefit.

Topics: Atorvastatin; Cardiovascular Diseases; Cause of Death; Chemical and Drug Induced Liver Injury; Double-Blind Method; Fluvastatin; Headache; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney Diseases; Lovastatin; Middle Aged; Muscular Diseases; Nausea; Neoplasms; Network Meta-Analysis; Placebos; Pravastatin; Randomized Controlled Trials as Topic; Risk Assessment; Rosuvastatin Calcium; Simvastatin; Withholding Treatment

In patients undergoing vascular surgery there is a high incidence of adverse cardiac events, due to sudden coronary plaque rupture. The non-lipid lowering or pleiotropic effects of statins can help reduce adverse cardiovascular events associated with vascular surgery.. The evidence for perioperative use of fluvastatin, as well as other statins, in high-risk surgery patients is summarized in this review. Data on pharmacokinetics and metabolism is presented, together with considerations on possible drug interactions in the perioperative period.. The reader will gain a comprehensive understanding of the existing safety and efficacy data for fluvastatin and other statins in the perioperative period. The practical considerations of perioperative fluvastatin therapy will be presented, including potential side-effects and management of the early non-oral phase immediately post surgery. Finally, advice on when to initiate therapy and safety recommendations are offered.. In patients scheduled for high-risk vascular surgery, fluvastatin improves postoperative outcome, reducing the incidence of myocardial damage by approximately 50% in the first 30 days following vascular surgery. In comparison with placebo, fluvastatin was not associated with a rise in liver enzymes or creatine kinase levels. To bridge the non-oral phase, an extended-release formula is recommended.

Topics: Administration, Oral; Anesthetics; Biotransformation; Cardiac Surgical Procedures; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme System; Delayed-Action Preparations; Drug Interactions; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Male; Muscular Diseases; Myocardial Ischemia; Plaque, Atherosclerotic; Postoperative Complications; Premedication; Randomized Controlled Trials as Topic; Risk; Rupture, Spontaneous; Substance Withdrawal Syndrome

The "statins," or hydroxymethylglutaryl coenzyme A (HMG-CoA)-reductase inhibitors, are a generally safe class of drugs that are widely used throughout the world and are rarely associated with severe hepatotoxicity. In this article, two cases of severe hepatotoxicity attributed to statin use are presented. In addition, a detailed summary of previously published cases of statin hepatotoxicity and the risks and benefits of statins in patients with chronic liver disease are presented. Drug-induced liver injury (DILI) from statins typically presents with an acute hepatocellular liver injury pattern, although mixed or cholestatic injury patterns have also been reported. Nonspecific autoantibodies as well as clinical, laboratory, and histological features of an autoimmune-like hepatitis may be present in some patients with statin hepatotoxicity. Despite their widespread use, acute liver failure and death have rarely been reported in patients with statin hepatotoxicity. Multiple retrospective studies as well as a large prospective randomized controlled trial demonstrate that statins can safely be given to hyperlipidemic patients with compensated chronic liver disease.

Topics: Adult; Aged; Aged, 80 and over; Atorvastatin; Autoimmunity; Biomarkers; Biopsy; Chemical and Drug Induced Liver Injury; Chronic Disease; Fatty Acids, Monounsaturated; Female; Fluvastatin; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Indoles; Liver; Liver Diseases; Male; Middle Aged; Practice Guidelines as Topic; Pyrroles; Risk Assessment; Treatment Outcome; Young Adult

We sought to assess the relationship between the magnitude of low-density lipoprotein cholesterol (LDL-C) lowering and rates of elevated liver enzymes, rhabdomyolysis, and cancer.. Although it is often assumed that statin-associated adverse events are proportional to LDL-C reduction, that assumption has not been validated.. Adverse events reported in large prospective randomized statin trials were evaluated. The relationship between LDL-C reduction and rates of elevated liver enzymes, rhabdomyolysis, and cancer per 100,000 person-years was assessed using weighted univariate regression.. In 23 statin treatment arms with 309,506 person-years of follow-up, there was no significant relationship between percent LDL-C lowering and rates of elevated liver enzymes (R2 <0.001, p = 0.91) or rhabdomyolysis (R2 = 0.05, p = 0.16). Similar results were obtained when absolute LDL-C reduction or achieved LDL-C levels were considered. In contrast, for any 10% LDL-C reduction, rates of elevated liver enzymes increased significantly with higher statin doses. Additional analyses demonstrated a significant inverse association between cancer incidence and achieved LDL-C levels (R2 = 0.43, p = 0.009), whereas no such association was demonstrated with percent LDL-C reduction (R2 = 0.09, p = 0.92) or absolute LDL-C reduction (R2 = 0.05, p = 0.23).. Risk of statin-associated elevated liver enzymes or rhabdomyolysis is not related to the magnitude of LDL-C lowering. However, the risk of cancer is significantly associated with lower achieved LDL-C levels. These findings suggest that drug- and dose-specific effects are more important determinants of liver and muscle toxicity than magnitude of LDL-C lowering. Furthermore, the cardiovascular benefits of low achieved levels of LDL-C may in part be offset by an increased risk of cancer.

Topics: Chemical and Drug Induced Liver Injury; Cholesterol, LDL; Dose-Response Relationship, Drug; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Indoles; Liver Diseases; Lovastatin; Neoplasms; Pravastatin; Rhabdomyolysis; Simvastatin

Clinical experience with fluvastatin in > 1,800 North American patients treated for an average of 61 weeks has shown it to be safe and well tolerated. Frequencies of transaminase and creatine kinase elevations compare favorably with those observed during long-term administration of other 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors. Further, whereas frank rhabdomyolysis has been encountered with treatment with all other HMG-CoA reductase inhibitors, this syndrome has not been observed to date with fluvastatin in studies here or abroad; a single case of myopathy, which was probably related to physical exertion, was reported in a patient receiving fluvastatin. Although dyspepsia was observed more commonly in fluvastatin patients the incidence, along with that of other adverse events (e.g., headache), and the number of treatment discontinuations proved statistically indistinguishable from those of placebo controls. Whether the favorable safety profile of fluvastatin is related to this synthetic agent's unique biopharmaceutical profile is a matter of ongoing long-term inquiry.

Topics: Anticholesteremic Agents; Biopharmaceutics; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drug Interactions; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Muscular Diseases; Safety

Hepatitis is one of earlier, but serious, signs of liver damage. High doses of statins for a long time can induce hepatitis. This study aimed to evaluate and compare the therapeutic potential of thymoquinone (TQ) and bee pollen (BP) on fluvastatin (F)-induced hepatitis in rats. Rats were randomly divided into: group 1 (G1, control), G2 (F, hepatitis), G3 (F + TQ), G4 (F + BP), and G5 (F + TQ + BP). Single treatment with TQ or BP relieved fluvastatin-induced hepatitis, with best effect for the combined therapy. TQ and/or BP treatment significantly (1) reduced serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma glutamyl transpeptidase, and total bilirubin, (2) decreased malondialdehyde levels and increased level of reduced glutathione, and activities of glutathione peroxidase and catalase in the liver, (3) improved liver histology with mild deposition of type I collagen, (4) increased mRNA levels of transforming growth factor beta 1, nuclear factor Kappa B, and cyclooxygenase 1 and 2, and (5) decreased tumor necrosis factor alpha and upregulated interleukin 10 protein in the liver. These data clearly highlight the ability of TQ and BP combined therapy to cause better ameliorative effects on fluvastatin-induced hepatitis than individual treatment by each alone.

Topics: Animals; Antioxidants; Bees; Benzoquinones; Biomarkers; Chemical and Drug Induced Liver Injury; Disease Management; Disease Susceptibility; Fluvastatin; Gene Expression; Hepatitis, Animal; Immunohistochemistry; Liver Function Tests; Oxidative Stress; Pollen; Rats; Treatment Outcome

BACKGROUND Fluvastatin, a commonly prescribed statin, is indicated for treatment of hypercholesterolemia in persons at high risk for coronary, cerebrovascular, and peripheral artery disease. However, there have been rare reports of liver injury or renal failure associated with use of fluvastatin. CASE REPORT We describe the case of a 69-year-old Saudi man with a medical history of diabetes mellitus and hypercholesterolemia for 2 years, on metformin, gliclazide modified release, daily aspirin, and simvastatin. Fluvastatin 40 mg daily was administered instead of simvastatin for 7 weeks before the patient was admitted to the hospital with fatigue, weakness, abdominal pain, loss of appetite, vomiting, itching, and elevated liver enzymes. Discontinuation of fluvastatin and other combined therapies led to a decrease in liver enzymes. He was diagnosed with fluvastatin-induced cholestatic liver injury and acute kidney disease. CONCLUSIONS The Naranjo scale indicates a probable relationship between cholestatic liver injury and fluvastatin, as well as a possible relationship between cholestatic injury and gliclazide and metformin. In our case report, we describe the synergistic effect of several factors in contributing to liver injuries, such as age, long-term gliclazide intake, and fluvastatin. Accordingly, we recommend close monitoring of patients' liver and kidney function, especially in the elderly and those with polypharmacy, while allowing sufficient time for the liver function to recover from a reversible reaction to fluvastatin.

Topics: Aged; Chemical and Drug Induced Liver Injury; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Simvastatin

Rats that consumed a high-fat and high-sucrose diet (HF diet) developed hepatic steatosis. Treatment of HF diet-fed rats with fluvastatin (8 mg/kg) was lethal, followed by an elevation in levels of plasma aspartate aminotransferase and creatine kinase activities and skeletal muscle toxicity. This study was conducted to determine whether nutritional status affects statin-induced adverse effects in rats. Fluvastatin treatment of rats fed the HF diet led to an increase in systemic exposure, suggesting altered metabolism and elimination. In fact, although hepatic multidrug resistance-associated protein (Mrp) 2 and multidrug resistance (Mdr) 1b protein levels were not significantly changed by fluvastatin treatment for 8 days of rats fed a HF diet, the organic anion-transporting protein (Oatp) 1, Mrp3, CYP1A, CYP2C, UDP-glucuronosyltransferase (UGT) 1A1, and UGT1A5 protein levels were moderately decreased and the Oatp2, CYP3A, and UGT2B1 protein levels were markedly suppressed. No significant difference in the baseline level of Oatp1, Oatp2, Mrp2, Mrp3, Mdr1b, CYP1A, CYP2C, CYP3A, UGT1A1, UGT1A5, or UGT2B1 protein was found between the standard diet- and HF diet-fed groups. In addition, the mRNA levels of Oatp2, CYP2C11, and CYP3A1/2 were markedly decreased in HF diet-fed and fluvastatin-treated rats. There was no significant difference in the glucuronidation activities against fluvastatin among the four groups. In liver cell nuclei, levels of constitutive androstane receptor, pregnane X receptor, and hepatocyte nuclear factor 4α proteins were decreased in fluvastatin-treated HF diet-fed rats, which correlated with the decrease in Oatp2, CYP2C, and CYP3A. Taken together, these results indicate that nutritional status may influence adverse effects of fluvastatin by increasing systemic exposure through modulation of hepatic uptake and elimination.

Topics: Animals; Cells, Cultured; Chemical and Drug Induced Liver Injury; Dietary Fats; Dietary Sucrose; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Liver; Liver Function Tests; Male; Metabolic Detoxication, Phase I; Metabolic Detoxication, Phase II; Microsomes, Liver; Multidrug Resistance-Associated Protein 2; Muscular Diseases; Nutritional Status; Organic Anion Transporters; Rats; Rats, Wistar

Signal detection is a crucial element in recognising new adverse drug reactions (ADRs) as soon as possible. HMG-CoA reductase inhibitors ('statins'), the most potent cholesterol-lowering drugs, are generally well tolerated but can occasionally lead to liver toxicity. Pre- and postmarketing studies on statins revealed an incidence of 0.1-3% elevation in hepatic transaminase levels. However, these elevations are asymptomatic, reversible, dose related or probably due to other causes. Postmarketing studies clearly showed the lack of evidence of hepatotoxicity from statins, apart from some isolated case reports of serious hepatic damage described in the literature. It is still unclear whether serious hepatic reactions are dose related and more frequent than the expected rate in the general population.. In this study, the hypothesis that fluvastatin could cause serious liver injuries more than the other statins is investigated, in the light of a quantitative and qualitative signal analysis, drug consumption data and evidence from the literature.. The Italian Interregional Group of Pharmacovigilance (Gruppo Interregionale di Farmacovigilanza; GIF) is an example of signal detection within the Italian spontaneous ADR reporting system. The GIF database holds reports of suspected ADRs submitted by five Italian pharmacovigilance regional centres. In the GIF database, all reports of suspected ADRs are classified according to the WHO criteria for causality assessment. The reactions are coded according to the WHO Adverse Reaction Terminology and classified as serious or non-serious events on the basis of the WHO Critical Term List. Every 6 months the GIF database is analysed to extract potential signals through a qualitative case-by-case analysis and using a quantitative methodology called proportional reporting ratio (PRR). This methodology permitted us to identify the potential signal 'fluvastatin and hepatic reactions'.. At 31 December 2004, the GIF database contained 35 757 reports with an annual reporting rate of 170 reports per million inhabitants. We found a total of 1260 reports of ADRs related to statins, including 178 of hepatic reactions. Sixty-nine reports were attributed to fluvastatin, which showed the highest PRR in comparison with the other statins. Fluvastatin was associated with 33 serious reactions, mainly hepatitis and cholestatic hepatitis. The number of reports of severe hepatotoxicity associated with fluvastatin started to increase from 2002. About half of them did not report other suspected or concomitant drugs and in one third the hepatotoxicity occurred after <1 month of therapy. Twenty-seven out of 33 patients were female, and fluvastatin was administered at 80 mg/day in 81% of cases reporting complete data on drug dosage.. In the literature, serious hepatic reactions are rarely described in patients taking statins; however, data gathered by GIF suggest that cases of hepatotoxicity are reported more often than expected. In addition, GIF data seem to reveal that fluvastatin is more likely to cause hepatic reactions than the other statins. However, this is a preliminary signal and future evaluations are certainly needed to confirm it and to quantify this possible risk.

Topics: Adverse Drug Reaction Reporting Systems; Aged; Chemical and Drug Induced Liver Injury; Databases, Factual; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Italy; Male; Middle Aged; Signal Processing, Computer-Assisted